TAVR Patients With Nickel Allergy

Abstract

Transcatheter aortic valve replacement (TAVR) is a preferred treatment option for many patients with severe aortic stenosis, but concerns exist regarding safety in patients with nickel allergy due to metallic valve frames. We report a series of 7 patients with a history of nickel allergy who underwent TAVR. Preprocedural allergy evaluation varied, including patch testing or direct skin contact with valve fragments. None of the patients experienced severe allergic reactions, and all remained free of significant nickel allergy–related symptoms during follow-up. A review of the literature identified only 1 prior case of severe nickel hypersensitivity requiring TAVR valve explantation. Importantly, no consistent correlation was observed between patch test results and clinical outcomes. These findings suggest that TAVR can likely be safely performed in patients with nickel allergy and that routine preprocedural patch testing has questionable utility. Further research is needed to clarify long-term outcomes in this population.

Take-Home Messages

• •Many commercially available TAVR valves contain metallic frames with varying amounts of nickel, raising concerns about the safety of implanting these devices in patients with a history of nickel allergy.
• •There is a lack of consistent relationship between cutaneous testing and clinical outcomes; therefore, the utility of patch testing or direct skin contact testing with the valve frame is uncertain.
• •Based on our experience and literature review, patients with nickel allergy appear to be able to safely undergo TAVR with a low risk of any postprocedural severe allergic symptoms.

Transcatheter aortic valve replacement (TAVR) has become a preferred treatment option for many patients with severe aortic stenosis across various surgical risk profiles. An often-overlooked related issue is concern regarding potential metal allergies, particularly nickel hypersensitivity, due to the use of metallic frame prostheses in many commercially available TAVR valves. Nickel, a common component of metal alloys used in valve frames, could possibly trigger allergic reactions in sensitized individuals. The prevalence of nickel allergy in the general population is approximately 20%, posing a significant challenge for patients requiring implantation of metallic or metal-containing devices, such as those used in TAVR.¹ Although nickel hypersensitivity related to various devices has been described, the incidence in TAVR cases and the prognostic role of patch testing and outcomes remain unknown. We report what is, to our knowledge, the largest case series of TAVR in patients with a history of nickel allergy.

Case Presentations

Patient #1

An 81-year-old woman with essential hypertension, coronary artery disease, paroxysmal atrial fibrillation, and severe aortic stenosis was evaluated for TAVR. The history of nickel allergy was based on multiple episodes of irritation from earrings. Before valve replacement, she was referred to an allergist and had undergone preprocedural patch testing for contact dermatitis, which showed negative results for nickel and titanium. The patient underwent TAVR with a 26-mm Medtronic Evolut Pro Plus valve made of porcine pericardial tissue. She was asymptomatic and free of nickel allergy–related symptoms 2 years postprocedure.

Patient #2

A 74-year-old woman with essential hypertension, persistent atrial fibrillation, chronic lymphocytic leukemia, and severe aortic stenosis presented for TAVR evaluation. She reported a significant nickel allergy, and a fragment of an Edwards SAPIEN valve frame was taped to her arm with no irritation after 48 hours. She successfully underwent TAVR with a 23-mm Edwards SAPIEN 3 valve. Five months postprocedure, she remained free of allergy symptoms.

Patient #3

A 66-year-old woman with a history of surgical aortic valve replacement (SAVR) and nickel allergy was evaluated for TAVR due to bioprosthetic aortic valve stenosis. Patch testing confirmed nickel sensitivity. Despite recommendations for redo SAVR, the patient opted for TAVR and underwent a valve-in-valve procedure with a 23-mm Medtronic Evolut FX bioprosthetic valve. One year later, the patient remained asymptomatic with no evidence of allergic reactions.

Patient #4

A 92-year-old woman with essential hypertension, atrial fibrillation, and heart failure with preserved ejection fraction presented with severe aortic stenosis. She reported mild nickel allergy symptoms, including itching with earrings. Given the mild nature of her allergy, she underwent TAVR with a 29-mm Medtronic Evolut Pro valve. Three months postprocedure, she presented with shortness of breath and abdominal bloating, which were attributed to heart failure exacerbation related to diuretic noncompliance. The transthoracic echocardiogram at that time showed a well-seated prosthetic valve with normal function. The patient died 3 years later from sepsis.

Patient #5

A 78-year-old woman with hypertension and severe aortic stenosis was evaluated for TAVR. Because of a history of contact dermatitis to nickel, the decision was made to use an Edwards SAPIEN 3 valve, based on a lower nickel content than the available alternative valves. At 2-month follow-up, she was found to have potential valve mismatch on transthoracic echocardiography. Unfortunately, the patient was lost to follow-up after transesophageal echocardiography was ordered.

Patient #6

An 80-year-old woman with hypertension, hyperlipidemia, and severe aortic stenosis was evaluated for TAVR. She reported a single episode of contact dermatitis from jewelry and had been told that she had a nickel allergy. Given high surgical risk, a decision was made to proceed with TAVR. She underwent successful TAVR with a 26-mm Medtronic Evolut Pro valve. Two years later, she presented with a generalized rash, which resolved after a course of prednisone. The patient died 5 years later due to malignancy without valve dysfunction on follow-up echocardiographic studies.

Patient #7

A 77-year-old woman with coronary artery disease, atrial fibrillation, chronic kidney disease, and severe aortic stenosis was evaluated for TAVR. Because of nickel allergy and prior contact dermatitis to costume jewelry, she was sent to an allergist. Patch test results for nickel were negative. She underwent TAVR with a 29-mm Medtronic Evolut FX valve. No allergy-related symptoms were reported postprocedure, although she was rehospitalized for heart failure decompensation without valve dysfunction on follow-up echocardiography. The patient died 3 months later due to multifocal pneumonia.

Discussion

Seven patients with a history of nickel allergy who underwent a TAVR procedure are presented. Table 1 compares the baseline characteristics, valve type, and clinical outcomes. The management of patients with nickel allergy undergoing TAVR presents a unique challenge, particularly due to the common use of metal frames in TAVR devices. Although nickel allergy history is a relatively common condition, its association with adverse reactions to metal prostheses is rare. Nonetheless, it remains a topic of concern due to its poorly defined nature, limited understanding, insufficient high-quality data, and the uncertainty surrounding its true incidence and clinical implications with TAVR implantation.

Table 1.

Summarization of Patients Undergoing TAVR With Nickel Allergy

Patient #	Age, y	History	Nickel Allergy	Valve Type	Outcome	Follow-Up
1	81	Hypertension, CAD, AF, severe aortic stenosis	Mild, confirmed earring infection	Medtronic Evolut Pro Plus (26 mm)	Asymptomatic, no allergy symptoms	2 y
2	74	Hypertension, persistent AF, CLL, severe aortic stenosis	Severe, earring irritation	Edwards SAPIEN 3 (23 mm)	Asymptomatic, no allergy symptoms	5 mo
3	66	SAVR, severe aortic stenosis, nickel allergy	Positive patch test	Medtronic Evolut FX (23 mm, valve-in-valve)	Asymptomatic, no allergy symptoms	1 y
4	92	Hypertension, HFpEF, atrial fibrillation, severe aortic stenosis	Mild, itching with earrings	Medtronic Evolut Pro (29 mm)	No allergy symptoms, unrelated GI complaints	3 y
5	78	Hypertension, severe aortic stenosis	Severe, multiple dermatitis reactions	Edwards SAPIEN 3 (26 mm)	Valve mismatch and early pannus or clot concerns, anticoagulation therapy	2-mo follow-up TTE, then lost to follow-up
6	80	Hypertension, hyperlipidemia, severe aortic stenosis	Mild, history of jewelry-induced rash	Medtronic Evolut Pro (26 mm)	Generalized rash 2 years after the procedure, which resolved with a course of prednisone	5 y
7	77	CAD, AF, CKD, HFpEF, severe aortic stenosis	History of skin reactions to costume jewelry	Medtronic Evolut FX (29 mm)	No allergy symptoms, rehospitalization for heart failure	3 mo

AF = atrial fibrillation; CAD = coronary artery disease; CKD = chronic kidney disease; CLL = chronic lymphocytic leukemia; GI = gastrointestinal; HFpEF = heart failure with preserved ejection fraction; SAVR = surgical aortic valve replacement; TTE = transthoracic echocardiography.

Much of the discussion on nickel hypersensitivity related to implants is based on conflicting data from various endovascular devices, including peripheral and coronary stents, septal closure devices, pacemaker devices, and neuroendovascular implants.² Based on earlier data on bare-metal stents, in-stent restenosis was associated with nickel hypersensitivity; however, subsequent prospective studies have not confirmed a causal relationship between nickel allergy and in-stent restenosis.² The occurrence of so-called device syndrome after interatrial shunt closure has been described in the past.³ In this study, 19.5% of patients undergoing catheter-based closure of interatrial shunts with either Amplatzer Occluders or the Premere Closure System (Abbott) were found to have a nickel allergy based on cutaneous patch testing. Among these patients, 89% had chest discomfort, exertional dyspnea, asthenia, and mild leukocytosis, postoperatively. Notably, these symptoms were absent in patients without nickel allergy (P < 0.001). In addition, the study reported a 5-fold increase in serum nickel levels during the 6-week closure period, which returned to baseline after 4 to 6 months (P < 0.01). The authors suggested that this mild immunologic response may have contributed to the observed symptoms. In addition, Sharma et al⁴ reported removal of 58 atrial septal defect/patent foramen ovale devices in patients with nickel allergy who experienced persistent, refractory “device-related” symptoms. After device removal, all patients reported improvement in fatigue, chest pain, headaches, and palpitations. Moreover, all patients noted an enhanced quality of life and greater overall satisfaction, with 42% experiencing complete resolution of symptoms. Systemic allergic contact dermatitis due to a GORE Cardioform Septal Occluder device that was replaced with a bovine patch atrial septal defect repair, given severe urticaria unresponsive to medical management, is also reported in the literature.⁵

Although a meta-analysis by Guéroult et al² suggests that nickel hypersensitivity is associated with an increased risk of adverse outcomes after the implantation of nickel-containing endovascular devices, no long-term studies have specifically examined outcomes in TAVR prostheses. There is a single case report in the literature showing a severe metal allergic reaction after TAVR.⁶ The patient presented 6 months after Edwards SAPIEN 3 valve implantation with recurrent fever, chills, and night sweats. Echocardiography revealed thickened leaflets, partial valve dehiscence, and a possible allergic reaction. The patient subsequently underwent surgery, where a dense inflammatory reaction around the aortic root was seen. The histopathology report revealed fibrosis and chronic inflammation confirming the diagnosis of a severe metal allergic reaction. Interestingly, before implantation, the patient had undergone non-reactive cutaneous testing with a SAPIEN 3 valve frame fragment. Another case report demonstrates successful Edwards SAPIEN 3 valve implantation in a patient with nickel allergy. Before the procedure, the patient had undergone patch testing with both Edwards SAPIEN 3 and Medtronic Evolut CoreValve valve frames, along with additional testing for nickel and cobalt sensitivity. Although the patch test results were positive for nickel and cobalt, there was no reaction to the valve frames at 96 hours. The patient subsequently underwent successful SAPIEN 3 implantation without any notable adverse reactions.⁷

Endovascular device–related reactions likely share a similar delayed (type IV) hypersensitivity mechanism with cutaneous immune responses. Although some metal ions can trigger immune response by forming metal-protein complexes, nickel has demonstrated that it may directly activate T-cell receptors, contributing to its higher rate of hypersensitivity compared with other metals.⁸ Several strategies to mitigate nickel exposure in patients with nickel allergy have been previously described, primarily favoring the use of non–nickel-containing valves or low–nickel-content valves for SAVR procedures. The nickel concentration of a given valve platform is inherently determined by the specific alloys used. The standard metal alloys used in commercially available transcatheter aortic valves include nitinol (Evolut/CoreValve system) and cobalt-chromium (SAPIEN valves). Similarly, newer-generation valves such as Navitor and Myval use similar alloys, including nitinol and cobalt-chromium (Table 2). Nitinol is a metal alloy primarily composed of nickel and titanium in nearly equiatomic proportions. Typically, the composition is approximately 50% to 55% nickel and 45% to 50% titanium, which is essential for the unique mechanical and functional properties. In addition, some variants of nitinol alloys may include other elements, such as cobalt. To minimize the risk of nickel ion release, these valves undergo specific surface treatment including chemical polishing (removal of any loose nickel from the surface) and passivation (coating of the valve with a protective titanium-oxide layer). Conversely, cobalt-chromium alloys contain approximately 60% cobalt, 25% to 30% chromium, and 5% to 7% molybdenum. Minor elements such as tungsten, nickel, iron, carbon, silicon, and manganese may be present in small amounts. The presence of nickel is typically very low (<0.5%), so these valves do not require specialized surface treatments. Instead, they rely on the inherent corrosion resistance and biocompatibility of the alloy itself.

Table 2.

Current Commonly Transcatheter Aortic Valve Devices in Use, Their Alloys, and Nickel Content

Valve Name	Deployment Method	Frame Material	Nickel Content
CoreValve/Evolut (Medtronic)	Self-expandable	Nitinol (Ni, Ti)	50%-55%
ACURATE neo/neo2 (Boston Scientific)
Portico/Navitor/Vision (Abbott Vascular)
SAPIEN 3/Ultra (Edwards Lifesciences)	Balloon-expandable	Cobalt-chromium (Co, Ni, Cr, Mo, Ti, Mn)	<0.5%
Myval/Octaco (Meril Life Sciences)

Landmark TAVR trials did not specify nickel allergy as an exclusion criterion; thus, the prevalence of nickel-allergic patients in these studies was unknown. However, despite the inclusion of patients with nickel allergy, no significant allergic reactions related to nickel exposure were reported, suggesting that such reactions were not a major concern in these trials. In contrast, the ACURATE investigational device exemption trial, designed to evaluate the ACURATE neo2 aortic valve system, excluded patients with a history of nickel allergy, and the Society for Cardiovascular Angiography & Interventions (SCAI) recommends against the implantation of nitinol devices in patients with a documented significant nickel allergy due to the risk of allergic reactions.⁹ Furthermore, according to the Food and Drug Administration (FDA), the CoreValve Evolut R and CoreValve Evolut Pro devices should not be used in patients with sensitivity to nickel.¹⁰ There are no specific recommendations related with other valve protheses.

Our 7 patients had no severe adverse events, raising the prospect that nickel allergy history should not be considered a major factor in TAVR evaluation. However, “device syndrome” may have been underreported where symptoms were not significant enough to prompt patients to seek medical care. The surface engineering techniques used in Evolut/CoreValve valves, along with the use of materials with lower nickel concentrations, such as those in SAPIEN valves, appear to be safe approaches in these scenarios. The discrepancy between our findings and a case reported in the literature, where a patient developed a severe allergic reaction requiring device explantation, raises important questions. Potential explanations include defective surface treatments leading to inadequate nickel release kinetics, an allergic reaction to other metals present in cobalt-chromium alloys, or an individual maladaptive immune response.

Conclusions

Based on these 7 cases, patients with nickel allergy appear to be able to safely undergo TAVR. This series highlights the lack of correlation between nickel allergy history and documented related adverse events. Moreover, a consistent relationship between cutaneous testing and clinical outcomes was not observed; therefore, the utility of preoperative nickel testing, either formal patch testing or direct skin contact testing with the valve frame, is questionable. Although the successful outcomes observed in this case series support the feasibility of TAVR in patients with nickel allergy, operators should take into account the SCAI's and FDA's advisory regarding the use of CoreValve devices in individuals with nickel allergy. Lastly, our findings may not be generalizable to the broader population, and further robust investigation is warranted to assess whether subclinical hypersensitivity reactions could lead to long-term consequences.

Declaration of AI and AI-Assisted Technologies in the Writing Process

During the preparation of this work, the author(s) used artificial intelligence for the construction of Table 1. After using this tool/service, the authors reviewed and edited the content as needed and take full responsibility for the content of the publication.

Funding Support and Author Disclosures

The authors have reported that they have no relationships relevant to the contents of this paper to disclose.